tbuckley/cabot-search huggingface dataset:
Left ventricular SGLT1 expression is upregulated in heart failure in humans and rat model
Authors: AA Sayour, M Ruppert, A Olah, BA Barta, E Zsary, K Benke, EM Horvath, I Hartyanszky, B Merkely, T Radovits
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Fund of Hungary; Ministry of Human Capacities of Hungary Introduction Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to contribute to cardiac pathological processes, whereas humans with functionally limited SGLT1 are at lower risk of developing heart failure (HF). The novel HF medications, SGLT2 inhibitors, non-selectively inhibit SGLT1 to different extent, therefore, characterization of its expression in disease conditions is relevant. Purpose To investigate left ventricular (LV) SGLT1 expression in humans with end-stage HF, and in a rat model of HF. Methods Myocardial LV samples were harvested from control subjects (Controls, n=9) undergoing valve surgery, and from patients with end-stage dilated cardiomyopathy (DCM, n=12) undergoing heart transplantation. The rat model of aorto-caval fistula (ACF, n=12) was used to induce HF with predominant LV dilation in rats during a course of 24 weeks; sham-operated animals served as controls (Sham-A, n=12). Echocardiography was used to assess LV structure and function prior to surgery in humans, as well as in rats at the end of the follow-up period. Western blotting was performed to characterize LV SGLT1 protein expression and to investigate the activity of the master regulators AMPK and ERK1/2. The extent of LV nitro-oxidative stress was quantified by immunohistochemistry (3-nitrotyrosine) in rats with HF. Results Both humans with DCM and rats with ACF-induced HF presented with severely dilated LVs compared to respective controls, whereas LV SGLT1 protein expression was significantly upregulated similarly by ~1.7-fold in both cases (both P&amp;lt;0.01). These increases in SGLT1 expressions were accompanied by significant reductions in ERK1/2 activating phosphorylation (both P&amp;lt;0.05), whereas AMPK activity was unaffected. In rats with HF, LV SGLT1 expression correlated significantly with the extent of myocardial nitro-oxidative stress (r=0.762, P=0.037). Conclusions LV SGLT1 expression is upregulated in HF in both humans and small animals, and ERK1/2 shows a concomitantly reduced activity. LV SGLT1 expression correlates with the extent of nitro-oxidative stress, suggesting a possible pathological role in HF. Whether SGLT2 inhibitors exert direct cardiac actions via inhibition of myocardial SGLT1 needs to be elucidated.
HGG-58. SIOPE HGG Working Group approach to obtain consensus on management of paediatric high grade glioma across Europe
Authors: Géraldine Giraud, Elwira Szychot, Christof Kramm, Darren Hargrave, Dannis G van Vuurden
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: There is currently no European standard clinical practice on the management of paediatric HGG (pHGG). AIMS: To develop approved clinical recommendations for the management of pHGG reflecting current best practice, with the ultimate aim of improved outcomes. METHODS: An open questions survey was performed to establish the status quo regarding standards of care in pHGG across Europe. National coordinators from 33 countries were invited to participate in the process. RESULTS: 32 out of 33 countries completed the survey. Substantial areas of agreement were reached. All 32 countries agreed that hemispheric pHGG should be treated with radiotherapy and adjuvant chemotherapy after surgical resection. 30/32 (94%) countries proposed initial radiotherapy with concomitant temozolomide where 23/32 (72%) countries recommended a complementary adjuvant chemotherapy (Lomustine, Valproic acid, or Nivolumab). 32 countries agreed H3K27M diffuse midline glioma DMG, including DMG of the pons (DIPG), should be treated with radiotherapy. 10/32 (31%) countries proposed radiotherapy alone at diagnosis. There was no consensus on the role of adjuvant chemotherapy; temozolomide was recommended in 9/32 (28%), while mTOR inhibitor in 7/32 (22%) countries. A biopsy of DIPG was routinely offered in 18/32 (56%) countries, while in 4 countries was considered on an individual basis. Six countries never performed a biopsy. Re-irradiation at the relapse was consensual in 26/32 (81%) countries. Certain areas of divergence were identified. A Delphi method is being employed to reach a general consensus on those areas. CONCLUSION: This two-step approach will help us to set up the European guidelines on the management of pHGG based on the current best standard of care. This approach will also identify areas, which should be the focus of future collaborative studies. Such efforts will ultimately translate into improved patient outcomes.
Omicron BA.1 breakthrough infection drives cross-variant neutralization and memory B cell formation against conserved epitopes
Authors: Jasmin Quandt, Alexander Muik, Nadine Salisch, Bonny Gaby Lui, Sebastian Lutz, Kimberly Krüger, Ann-Kathrin Wallisch, Petra Adams-Quack, Maren Bacher, Andrew Finlayson, Orkun Ozhelvaci, Isabel Vogler, Katharina Grikscheit, Sebastian Hoehl, Udo Goetsch, Sandra Ciesek, Özlem Türeci, Ugur Sahin
Journal: Science Immunology (2022)

Omicron is the evolutionarily most distinct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC) to date. We report that Omicron BA.1 breakthrough infection in BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2, and previous SARS-CoV-2 VOCs but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding memory B (B
Survival of patients with neuroblastoma before versus after reduction of therapy due to the change in age cut-off from 12 to 18 months in Children’s Oncology Group (COG) risk stratification.
Authors: Wendy B. London, Hannah Bender, Meredith Irwin, Michael D. Hogarty, Robert P. Castleberry, John M. Maris, Pei-Chi Kao, Arlene Naranjo, Susan Lerner Cohn
Journal: Journal of Clinical Oncology (2022)

10013 Background: In 2006, COG reclassified subgroups of toddlers diagnosed with neuroblastoma from high-(HR) to intermediate-risk (IR), when the age cut-off for increased risk was raised from 365 days (12 mo) to 547 days (18 mo) (London, J Clin Onc 2005). The aim of this retrospective study was to determine if excellent outcome was maintained after a reduction of therapy. Methods: Children &lt; 3 yrs old at diagnosis, enrolled on a COG biology study from 1990-2018, were eligible (n = 9,189). Therapy was reduced for two “cohorts of interest” based on the age cut-off change: 365-546 days old with INSS stage 4, MYCN not amplified, favorable INPC, hyperdiploid tumors (12-18mo/Stage4/FavBiology); and, 365-546 days old with INSS stage 3 tumors with non-amplified MYCN and unfavorable INPC (12-18mo/Stage3/NotAmp/UnfavINPC). Log rank tests compared event-free (EFS) and overall survival (OS) curves. Results: In the cohorts of interest, patient (pt) characteristics were similar for ≤2006 vs &gt; 2006. For 12-18mo/Stage4/FavBiology, 5-year EFS and OS (± std error) before (≤2006; n = 40) versus after (&gt; 2006; n = 55) the reduction in therapy were similar: 89±5.1% versus 87±4.6% (p = 0.7), and 89±5.1% versus 94±3.2% (p = 0.4), respectively (Table). For 12-18mo/Stage3/NotAmp/UnfavINPC, the 5-year EFS and OS were both 100%, before (n = 6) and after (n = 4) 2006. For the combined cohorts for ≤2006 versus &gt; 2006, EFS and OS were 91±4.4% versus 88±4.3% (p = 0.6), and 91±4.5% versus 95±2.9% (p = 0.5), respectively. Within HR pts diagnosed ≤2006, EFS/OS were 91±4.4%/91±4.5% for (12-18mo/Stage4/FavBiology plus 12-18mo/Stage3/NotAmp/UnfavINPC) vs 38±1.3%/43±1.3% for all other HR pts &lt; 3 yrs old (p &lt; 0.0001; Table). Within IR pts diagnosed &gt; 2006, EFS/OS were 88±4.3%/95±2.9% for (12-18mo/Stage4/FavBiology plus 12-18mo/Stage3/NotAmp/UnfavINPC) vs 88±0.9%/95±0.6% for all other IR pts &lt; 3 yrs old (p = 0.9). Conclusions: Our 19 year study demonstrates that excellent outcome is maintained among toddlers with Stage4/FavBiology and Stage3/Not Amp/Unfav INPC neuroblastoma with a significant reduction of therapy from high- to intermediate-risk treatment. Importantly, pts were likely spared acute toxicity and late effects known to be associated with HR therapy. Efforts to identify additional pt cohorts who may not require HR therapy to achieve long-term survival are critical to improve the long-term health of children with neuroblastoma. [Table: see text]
HGG-13. Combined CDK inhibition and arginine-deprivation as targeted therapy for arginine-auxotrophic glioblastoma multiforme cells
Authors: Christin Riess, Katharina del Moral, Adina Fiebig, Philipp Kaps, Charlotte Linke, Burkhard Hinz, Anne Rupprecht, Markus Frank, Tomas Fiedler, Dirk Koczan, Sascha Troschke-Meurer, Holger N Lode, Nadja Engel, Carl Friedrich Classen, Claudia Maletzki
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION/BACKGROUND: Glioblastoma multiforme show constitutive activation of cyclin-dependent kinases (CDKs) or arginine auxotrophy. This renders tumor cells vulnerable towards arginine-depleting substances, such as arginine deiminase from Streptococcus pyogenes (SpyADI). Previously, we confirmed the susceptibility of patient-derived GBM cells towards administration of SpyADI as well as CDK inhibitors (CDKis). To improve effects, we applied a sequential (SEQ) CDKi/SpyADI approach to examine mechanistic insights and drug susceptibility. MATERIALS AND METHODS: Three arginine-auxotrophic patient-derived GBM lines with different molecular characteristics were cultured in 2D and 3D (spheres and glioma stem-like cells (GSC)) and effects of this combined CDKi/SpyADI approach were analyzed. This included viability staining via Calcein AM in 2D and 3D-Glo in 3D culture and cell death analysis via flow cytometry. Therapy-induced morphological changes were identified with transmission electron microscopy (TEM). Besides, 3D-invasiveness, cellular stress, and DNA damage responses were measured. RESULTS: All SEQ-CDKi/SpyADI combinations yielded synergistic antitumoral effects, characterized by impaired cell proliferation, invasiveness, and viability. Notably, this SEQ-CDKi/SpyADI approach was most effective in 3D models. Mitochondrial impairment was demonstrated by increasing mitochondrial membrane potential and decreasing oxygen consumption rate along with extracellular acidification rate after abemaciclib/SpyADI monotherapy or its combination regimens. TEM confirmed damaged mitochondria and endoplasmic reticulum together with increased vacuolization under CDKi mono- and SEQ- CDKi/SpyADI combination therapy. SEQ-abemaciclib/SpyADI treatment suppressed the DSB repair system via NHEJ and HR, whereas SEQ-dinaciclib/SpyADI treatment increased γ-H2AX accumulation and induced Rad51/Ku80. The latter combination also activated the stress sensor GADD45 and β-catenin antagonist AXIN2. CONCLUSION: This study highlights the antitumoral potential of a combined SpyADI/CDKi approach. We show that sequential application of these substances has complex effects on mitochondrial dysfunction, invasiveness, and DNA-damage response. This provides a good starting point for further proof-of-concept studies to move forward with this strategy.
Patient efficacy in telehealth is moderated by distress among patients with cancer: A cross-sectional survey study.
Authors: Joseph William McCollom, Michelle Drouin, Mindy Flanagan, Rachel Pfafman
Journal: Journal of Clinical Oncology (2022)

1590 Background: The COVID-19 pandemic increased the use of telehealth to reduce exposure, which was critical for patients with cancer. The extent to which patients with cancer view telehealth visits as meeting their medical needs was investigated using a cross-sectional survey. Methods: Patients currently receiving cancer treatment at a single cancer institute who had had at least one telehealth visit were emailed an online survey. Response rate was 5% (94/1944). The survey measured patients’: 1) Emotional Thermometer (i.e. distress, anger, depression, anxiety, and need for help on a 0-10 scale); 2) Telehealth usability questionnaire (TUQ; 21-items with various subscales, like interaction quality; α=0.98).); and 3) Perceived Efficacy in Patient-Physician Interactions (PEPPI-5) scale (five items, e.g., “How confident are you in your ability to make the most of your visits with your doctors?”). Respondents completed the PEPPI-5 for in-person visits and for telehealth visits. Descriptive statistics were calculated for all measures. A generalized linear model was estimated predicting PEPPI-5 for telehealth visits from emotional thermometer and TUQ scores. The interaction between emotional thermometer and TUQ scores was estimated to test the hypothesis that emotional distress moderated the relationship between TUQ and efficacy in patient-provider interactions during telehealth visits. Results: Across all five thermometers, 30.8% (28/91) reported a high score on at least one metric. The most frequently reported high score was for anxiety, 23.3% (21/90) and least frequently reported high score was for anger, 12.2% (11/90). The mean TUQ score was 5.5 (SD=1.5) and mean PEPPI-5 score for telehealth visits was 8.1 (SD=2.4). As shown in Table, emotional thermometer scores did moderate the relation between TUQ and patient self-efficacy during telehealth visits. For high emotional thermometer scores, self-efficacy decreased as TUQ scores decreased. Conclusions: For patients experiencing high emotional distress, low comfort and ability with telehealth usability resulted in low patient self-efficacy in communicating with providers and getting medical needs met. Telehealth is a convenient and effective modality; however, in times of emotional distress for patients who are not familiar with telehealth, in-person clinic visits may result in greater patient self-efficacy.[Table: see text]
Responses to telehealth expansion for older adults with cancer during the COVID-19 pandemic.
Authors: Robin T Higashi, Bella Etingen, Suzanne Cole, John C. Mansour, John W. Sweetenham, Jessica L. Lee, Timothy P. Hogan
Journal: Journal of Clinical Oncology (2022)

1591 Background: Synchronous video visits (“telehealth”) were rapidly adopted to facilitate provision of cancer care during the COVID-19 pandemic, with little time to comprehensively assess patient and provider needs. Attitudes toward telehealth use during active treatment (vs. survivorship care) were largely unknown, as were perceptions of, experiences with, and needed support for telehealth use among older adults with cancer. Older adults in particular may face increased vulnerability to inequities in access to care due to limited digital literacy. Methods: We conducted surveys and semi-structured interviews with providers, staff, and older patients (age ≥60) from a comprehensive cancer center. Data collection occurred between Dec 2020 - Nov 2021. Results: We completed a total of 106 provider/staff surveys, 128 patient surveys, 20 provider/staff interviews, and 15 patient interviews. A majority of surveyed providers/staff felt that telehealth should “definitely be offered” during treatment-phase encounters (55.9% treatment follow-up; 69.1% results communication; 70.2% discussing treatment side effects). Similarly, most patients indicated they would be willing to have video visits with a member of their care team for: discussing treatment side-effects (73.5%), results communication (69.6%), and treatment follow-up (65.7%). Patients reported experiencing challenges with joining video visits (29%) and understanding the telehealth process (28%). Similarly, less than a third (30.8%) of providers/staff agreed or strongly agreed that the institution did a good job of preparing patients for their first telehealth encounter. Patients felt the institution should do more to communicate the advantages of telehealth to older adults in handouts and videos, which included: engaging multiple family members in critical appointments (e.g., treatment decisions, end-of-life), seeing their doctor when they were too sick to travel, and reducing potential exposure to infectious disease at the clinic. Participants suggested several strategies to assist patients with limited digital literacy: offering video tutorials of the connection process, creating “fake appointments” to practice online connections, and hiring a digital navigator to assist with technical difficulties and setup of the online portal. Despite challenges, a majority of surveyed patients (65.7%) and providers/staff (76.9%) intend to continue using telehealth after the COVID-19 pandemic passes. Conclusions: Use of telehealth for cancer care was received positively by older patients and providers/staff. Taking targeted steps to enhance implementation could reduce barriers to care, including among older adults and other populations with limited digital literacy, thereby promoting greater equity of access to telehealth benefits beyond the pandemic.
Genetic alterations in tumor tissue and cell-free DNA in patients with papillary thyroid carcinoma at initial surgery.
Authors: Ellen Shannon Story, Hsih-Te Yang, Ashley Stewart, Carol J. Farhangfar, Brittany Neelands, Nury Steuerwald, Erin E Donahue, James Thomas Symanowski, Zvonimir Milas, Daniel Brickman, Catherine Frenkel, Shwetha Sudhakar
Journal: Journal of Clinical Oncology (2022)

e18083 Background: The value of sequencing cell-free DNA (cfDNA) from patients with papillary carcinoma of the thyroid (PTC) is controversial. Studies utilizing whole-exome sequencing (WES) or single-gene detection methods have reported lower mutational yield in cfDNA in PTC compared with other cancers. Alternatively, mutational analyses of anaplastic thyroid carcinoma (ATC), which is thought to evolve from PTC, demonstrate high levels of mutated cfDNA. We report on mutations in tumor and cfDNA at initial surgery for PTC, correlate with clinicopathologic status and further characterize the mutational landscape of these tumors in tissue and blood utilizing deep-sequencing panel testing. Methods: 50 patients were enrolled 2017-2020. Tempus xT (648 genes) and xF (105 genes) panels were used to prepare next generation sequencing libraries from tissue and blood samples, respectively. Cell-free DNA (cfDNA) sequencing depth average is 20,000x (raw reads)/5,000x (unique reads). Results: More than half of the patients had pT3-T4 tumors and/or local metastases and one had distant metastasis. 47/47 (100%) of processable tissue samples and 40/49 (81.6%) of blood samples yielded at least one relevant mutation. BRAF V600E was found in 77% of tissue and 8% of cfDNA, while mutated TERT was detected in 17% of tissue and none of the blood samples. The most frequently mutated genes in cfDNA were KMT2A (18% of blood samples, 6 % tissue), ATM (12% blood, 6% tissue), and TP53 (12% blood, 2 % tissue). There was marked mutational heterogeneity among samples, and a range of alterations representing multiple oncogenic pathways. Conclusions: Patients at initial surgery demonstrated highly mutated tissue DNA, including BRAF, TERT and other mutations known to be found in PTC. The most frequent tissue mutations were found at higher rates than previously reported by WES, which may reflect the sensitivity of targeted deep sequencing versus WES, and possibly a selection bias of more advanced PTC. A high percentage of cfDNA samples yielded mutations relevant to thyroid cancer, and the absence of TERT is consistent with prior studies. Mutations and co-mutations associated with de-differentiation and worse outcomes were demonstrated in both tissue and cfDNA. Interestingly, mutations more common in ATC than PTC, such as TP53, were detected in cfDNA, often without primary tumor correlate. Since mutations associated with aggressive behavior may be found in metastatic foci while not detected in the primary tumor, we conclude that cfDNA may reveal prognostic information important for the development of surveillance strategies in selected patients with residual PTC after surgery who may be at risk for poor outcomes.
Machine Learning for the Identification of a Common Signature for Anti–SSA/Ro 60 Antibody Expression Across Autoimmune Diseases
Authors: Nathan Foulquier, Christelle Le Dantec, Eleonore Bettacchioli, Christophe Jamin, Marta Alarcón-Riquelme, Jacques-Olivier Pers, Lorenzo Beretta, Barbara Vigone, Alain Saraux, Valérie Devauchelle‐pensec, Divi Cornec, Sandrine Jousse‐joulin, Bernard Lauwerys, Julie Ducreux, Anne‐lise Maudoux, Carlos Vasconcelos, Ana Tavares, Esmeralda Neves, Raquel Faria, Mariana Brandão, Ana Campar, António Marinho, Fátima Farinha, Isabel Almeida, Miguel Ángel González‐gay, Ricardo Blanco Alonso, Alfonso Corrales Martínez, Ricard Cervera, Ignasi Rodríguez‐pintó, Gerard Espinosa, Rik Lories, Ellen de Langhe, Nicolas Hunzelmann, Doreen Belz, Torsten Witte, Niklas Baerlecken, Georg Stummvoll, Michael Zauner, Michaela Lehner, Eduardo Collantes, Rafaela Ortega‐castro, Mª Angeles Aguirre‐zamorano, Alejandro Escudero‐contreras, Mª Carmen Castro‐villegas, Yolanda Jiménez Gómez, Norberto Ortego, María Concepción Fernández Roldán, Enrique Raya, Inmaculada Jiménez Moleón, Enrique de Ramon, Isabel Díaz Quintero, Pier Luigi Meroni, Maria Gerosa, Tommaso Schioppo, Carolina Artusi, Carlo Chizzolini, Aleksandra Dufour, Donatienne Wynar, Laszló Kovács, Attila Balog, Magdolna Deák, Márta Bocskai, Sonja Dulic, Gabriella Kádár, Falk Hiepe, Velia Gerl, Silvia Thiel, Manuel Rodriguez Maresca, Antonio López‐berrio, Rocío Aguilar‐quesada, Héctor Navarro‐linares, Yiannis Ioannou, Chris Chamberlain, Jacqueline Marovac, Marta Alarcón Riquelme, Tania Gomes Anjos, Concepción Marañón, Lucas Le Lann, Quentin Simon, Bénédicte Rouvière, Nieves Varela, Brian Muchmore, Montserrat Alvarez, Jonathan Cremer, Nuria Barbarroja, Chary Lopez‐pedrera, Laleh Khodadadi, Qingyu Cheng, Anne Buttgereit, Zuzanna Makowska, Aurélie de Groof, Elena Trombetta, Tianlu Li, Damiana Alvarez‐errico, Katja Kniesch, Nancy Azevedo, Maria Hernandez‐fuentes, Pierre‐emmanuel Jouve, Jacques‐olivier Pers
Journal: Arthritis & Rheumatology (2022)

Anti-Ro autoantibodies are among the most frequently detected extractable nuclear antigen autoantibodies, mainly associated with primary Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), and undifferentiated connective tissue disease (UCTD). This study was undertaken to determine if there is a common signature for all patients expressing anti-Ro 60 autoantibodies regardless of their disease phenotype.
CCL17 acts as a novel therapeutic target in pathological cardiac hypertrophy and heart failure
Authors: Yang Zhang, Yicong Ye, Xiaoqiang Tang, Hui Wang, Toshiko Tanaka, Ran Tian, Xufei Yang, Lun Wang, Ying Xiao, Xiaomin Hu, Ye Jin, Haiyu Pang, Tian Du, Honghong Liu, Lihong Sun, Shuo Xiao, Ruijia Dong, Luigi Ferrucci, Zhuang Tian, Shuyang Zhang
Journal: The Journal of Experimental Medicine (2022)

Circulating proteomic signatures of age are closely associated with aging and age-related diseases; however, the utility of changes in secreted proteins in identifying therapeutic targets for diseases remains unclear. Serum proteomic profiling of an age-stratified healthy population and further community-based cohort together with heart failure patients study demonstrated that circulating C-C motif chemokine ligand 17 (CCL17) level increased with age and correlated with cardiac dysfunction. Subsequent animal experiments further revealed that Ccll7-KO significantly repressed aging and angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis, accompanied by the plasticity and differentiation of T cell subsets. Furthermore, the therapeutic administration of an anti-CCL17 neutralizing antibody inhibited Ang II-induced pathological cardiac remodeling. Our findings reveal that chemokine CCL17 is identifiable as a novel therapeutic target in age-related and Ang II-induced pathological cardiac hypertrophy and heart failure.